Process for reducing the crystal size of ondansetron hydrochloride dihydrate

ABSTRACT

The invention relates to a process for reducing the crystal size of ondansetron hydrochloride dihydrate produced by crystallization from solvent to a size which is suitable for effective distribution in a tablet blend, in particular 100% less that 250 μm. The ondansetron hydrochloride dihydrate is desolvated by drying at elevated temperature and reduced or atmospheric pressure and is then rehydrated.

This application is a Continuation of application Ser. No. 08/239,237,filed May 6, 1994, now abandoned, which is a Continuation of applicationSer. No. 08/005,736, filed Jan. 19, 1993, now U.S. Pat. No. 5,344,658,which is a Continuation of application Ser. No. 07/755,736, filed Sep.6, 1991, now abandoned, which is a Continuation of application Ser. No.07/544,644, filed Jun. 27, 1990, now abandoned.

This invention relates to a process for reducing the crystal size ofondansetron hydrochloride dihydrate. More particularly the processinvolves desolvation and resolvation.

Reduction of crystal size through solvation and desolvation has beendescribed previously, for instance for the compound griseofulvin (K.Sekiguchi et al., Chem. Pharm. Bull., 1968, 16, 2495-2502). Varioustechniques may be employed to effect desolvation such as drying at anelevated temperature and under vacuum, drying at an elevated temperatureand at atmospheric pressure, drying at ambient temperature under a highvacuum, freeze-drying, or drying over a desiccant. However, the preciseconditions of desolvation considerably affect the efficiency of thereduction in crystal size.

Ondansetron, the approved name for1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one,is a highly selective and potent antagonist of 5-hydroxytryptamine(5-HT) at 5-HT₃ receptors. Ondansetron, together with itsphysiologically acceptable salts and solvates, is described and claimedin British Patent No. 2153821B, and may be used in the treatment of avariety of conditions, including the nausea and vomiting induced bycancer chemotherapy and radiotherapy (as described, for example, inEuropean Patent Specification No. 226226A).

The preferred form of ondansetron for pharmaceutical formulation is thehydrochloride dihydrate. Ondansetron hydrochloride dihydrate may bepresented in a variety of formulations, one of which is as tablets fororal administration, when particularly suitable unit doses of the drugsubstance for the treatment of emesis are 5 mg and 10 mg.

In the tablet manufacturing process, ondansetron hydrochloride dihydrateis blended with suitable excipients, and the blend is then compressedinto tablets.

Since a low dose of drug substance per tablet is required, for example,5 mg of ondansetron hydrochloride dihydrate in a tablet of 125 mgcompression weight, the distribution of the drug substance in the blendis critical in obtaining individual tablets with the correct drugcontent. Uniform drug distribution in the tablet blend may be achievedusing drug substance of appropriate particle size. However, theondansetron hydrochloride dihydrate obtained by methods described in theart, i.e. that obtained by simple crystallization from an aqueoussolvent mixture with subsequent drying at ambient temperature andpressure contains particles which are too large (i.e. >250 μm) to givean homogeneous distribution of the drug substance in the tablet blend.Indeed if crystalline ondansetron hydrochloride dihydrate produced bysuch conventional methods were used in tablet manufacture, the tabletsso produced would not possess an acceptable drug content which, for a 5mg tablet, is 5 mg±0.25 mg of ondansetron hydrochloride dihydrate.

Attempts to mill crystals of ondansetron hydrochloride dihydrate toreduce their particle size have proved unsuccessful, for example,comminution milling of ondansetron hydrochloride dihydrate caused screenblockage of coarse and fine screens. Furthermore, although ondansetronhydrochloride dihydrate of particle size <250 μm can be obtained bypassing the substance through a 60 mesh sieve (as described, forexample, in UK Patent No. 2153821B), this method is not commerciallyviable.

We have now found a process which reduces the crystal size ofondansetron hydrochloride dihydrate produced by simple crystallizationfrom solvent (more particularly aqueous solvent mixtures) to a sizewhich is suitable for effective distribution of the drug substance inthe tablet blend.

Thus the invention provides a process for reducing the crystal size ofondansetron hydrochloride dihydrate obtained by simple crystallizationfrom solvent, more particularly an aqueous solvent mixture, to a sizewhich is suitable for effective distribution in a tablet blend, whichcomprises desolvating the said drug substance by drying at an elevatedtemperature and reduced or atmospheric pressure, and then rehydratingthe ondansetron hydrochloride so formed.

It is possible by means of the process according to the invention toreduce the crystal size of ondansetron hydrochloride dihydrate to theextent that the entire drug substance consists of particles of asufficiently small size (i.e. less than 250 μm, of which typically about80% by weight are less than 63 μm) to give an homogeneous distributionof the drug substance in the tablet blend.

Preferably, the ondansetron hydrochloride dihydrate obtained bycrystallization is desolvated by heating at a temperature greater than40° C. (e.g. 50° C.) and at reduced pressure (e.g. 200 torr or less) formore than 8 hours. Alternatively, the ondansetron hydrochloridedihydrate obtained by crystallization may be desolvated at ambientpressure by heating at a temperature of 50° C. or above (more preferably100° C.).

Most preferably, ondansetron hydrochloride dihydrate obtained bycrystallization is desolvated by heating at 50° C. at a pressure of 100torr for 2 hours.

The desolvation process may be carried out with or without mechanicalagitation.

The resultant ondansetron hydrochloride of reduced crystal size is thenrehydrated, for example, by placing it in a humidified atmosphere of,for example, air or nitrogen, at ambient temperature. Rehydration willgenerally be continued until there is no further gain in weight.

According to another aspect, the invention provides crystallineondansetron hydrochloride dihydrate characterized in that 100% of thecrystals have a size of less than 250 μm and at least 80% by weight ofthe crystals have a crystal size of less than 63 μm (as measured byair-jet sieve analysis).

According to a yet further aspect, the invention provides apharmaceutical composition in the form of tablets containing crystallineondansetron hydrochloride dihydrate as active ingredient characterizedin that 100% of the ondansetron hydrochloride dihydrate crystals have asize less than 250 μm and at least 80% by weight of the crystals have acrystal size of less that 63 μm (as measured by air-jet sieve analysis).Generally the composition will contain at least one physiologicallyacceptable carrier or excipient.

The invention is illustrated by the following examples. Temperatures arein °C. Crystal size was measured by air-jet sieve analysis.

EXAMPLE 11,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride dihydrate wherein the crystals are less than 250 μm

A solution of1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one(147 g) in a mixture of isopropanol (670 ml), water (250 ml) and glacialacetic acid (76 ml) at ca. 60° was clarified by filtration and dilutedwith more water (61 ml) and isopropanol (650 ml). The solution wastreated at 70° with 36% w/w hydrochloric acid (46 ml) and cooled to ca.5°. The resulting suspension was filtered and the filtered solid waswashed by displacement with isopropanol (600 ml) to give a solvent wetsolid (269 g). A portion of this solid (91 g) was dried at ca. 50° and200 torr for ca. 16h to give a solid (55 g).

A portion of the dried solid (26 g) was placed in a current ofhumidified air at ambient temperature until there was no further gain inweight and the title compound (29 g) was obtained.

    ______________________________________                                        Particle Size Distribution of Title Compound                                  Size (μm)                                                                            Cumulative % Undersize (by weight)                                  ______________________________________                                        45        43.4                                                                63        83.7                                                                90        97.6                                                                125       98.4                                                                180       99.6                                                                250       100.0                                                               ______________________________________                                    

EXAMPLE 21,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride dihydrate wherein the crystals are less than 250 μm

The previous preparation was repeated except that after collection byfiltration the solid was dried at ambient temperature and pressure togive large crystals (>45% by weight of crystals larger than 250 μm) of1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride dihydrate.

    ______________________________________                                        Particle Size Distribution of "Large Crystals"                                Size (μm)                                                                            Cumulative % Undersize (by weight)                                  ______________________________________                                        45        5.8                                                                 63        9.8                                                                 90        20.8                                                                125       26.7                                                                180       37.8                                                                250       50.6                                                                355       71.5                                                                500       90.9                                                                710       98.4                                                                1000      98.6                                                                ______________________________________                                    

A sample of this solid (26.9 g) was dried at ambient pressure and 100°for ca. 17h during which period the weight of the sample was reduced to24.3 g. The sample was then exposed to ambient temperatures andhumidities until it had regained its original weight to afford the titlecompound.

    ______________________________________                                        Particle Size Distribution of Title Compound                                  Size (μm)                                                                            Cumulative % Undersize (by weight)                                  ______________________________________                                        45        47.6                                                                63        94.8                                                                90        100.0                                                               ______________________________________                                    

EXAMPLE 31,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride dihydrate wherein the crystals are less than 250 μm.

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride dihydrate obtained by crystallization from a solvent wasdried at 52° and 100 torr for 24h and then rehydrated to give the titlecompound.

    ______________________________________                                        Particle Size Distribution of Title Compound                                  Size (μm)                                                                            Cumulative % Undersize (by weight)                                  ______________________________________                                        45        44.3                                                                63        83.2                                                                90        97.0                                                                125       98.8                                                                180       99.8                                                                250       100.0                                                               ______________________________________                                    

EXAMPLE 41,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride dihydrate wherein the crystals are less than 90 μm

1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride dihydrate obtained by crystallization from a solvent wasdried at 48° and 100 torr for 24h and then rehydrated to give the titlecompound.

    ______________________________________                                        Particle Size Distribution of Title Compound                                  Size (μm)                                                                              Cumulative % Undersize                                            ______________________________________                                        45          49.0                                                              63          92.4                                                              90          100.0                                                             ______________________________________                                    

I claim:
 1. A process for reducing the crystal size of ondansetronhydrochloride dihydrate produced by crystallization from solvent, inwhich said ondansetron hydrochloride dihydrate is desolvated by dryingat elevated temperature and reduced or atmospheric pressure and is thenrehydrated, wherein the resulting crystals are suitable for homogeneousdistribution in a tablet blend, said tablet providing a pharmaceuticallyacceptable formulation in effective amounts for treatment of ondansetronresponsive conditions.
 2. A process according to claim 1, in which saidondansetron hydrochloride dihydrate is prepared by crystallization froman aqueous solvent mixture.
 3. A process according to claim 1, in whichsaid ondansetron hydrochloride dihydrate is desolvated by heating at atemperature greater than 40° C. and at reduced pressure for more than 8hours.
 4. A process according to claim 3, in which said ondansetronhydrochloride dihydrate is desolvated by heating at a temperature ofabout 50° C. at a pressure of about 100 torr for about 24 hours.
 5. Aprocess according to claim 1, in which said ondansetron hydrochloridedihydrate is desolvated by heating at a temperature of 50° C. or aboveat ambient pressure.
 6. A process according to claim 5, in which saidtemperature is about 100° C.
 7. A process according to claim 1, in whichsaid ondansetron hydrochloride dihydrate is rehydrated in a humidifiedatmosphere at ambient temperature.
 8. A process for reducing the crystalsize of ondansetron hydrochloride dihydrate produced by crystallisationfrom solvent, in which said ondansetron hydrochloride dihydrate isdesolvated by drying at elevated temperature and reduced or atmosphericpressure and is then rehydrated, wherein the resulting crystals aresuitable for effective distribution in a tablet blend, said tabletproviding a pharmaceutically acceptable formulation in effective amountsfor treatment of ondansetron responsive conditions.
 9. A processaccording to claim 8, in which said ondansetron hydrochloride dihydrateis prepared by crystallisation from an aqueous solvent mixture.
 10. Aprocess according to claim 8, in which said ondandsetron hydrochloridedihydrate is desolvated by heating at a temperature greater than 40° C.and at reduced pressure for more than 8 hours.
 11. A process accordingto claim 10, in which said ondansetron hydrochloride dihydrate isdesolvated by heating at a temperature of about 50° C. at a pressure ofabout 100 torr for about 24 hours.
 12. A process according to claim 8,in which said ondansetron hydrochloride dihydrate is desolvated byheating at a temperature of 50° C. or above at ambient pressure.
 13. Aprocess according to claim 12, in which said temperature is about 100°C.
 14. A process according to claim 8, in which said ondansetronhydrochloride dihydrate is rehydrated in a humidified atmosphere atambient temperature.